Antitumor Activity Research Articles

Thiazole, isatin and phthalimide derivatives tested in vivo against cancer models: a literature review of the last six years.

Cancer is a disease characterized by the abnormal multiplication of cells and is the second leading cause of death in the world. The search for new effective and safe anticancer compounds is ongoing due to factors such as low selectivity, high toxicity, and multidrug resistance. Thus, heterocyclic compounds derived from isatin, thiazole and phthalimide that have achieved promising in vitro anticancer activity have been tested in vivo and in clinical trials. This review focused on the compilation of promising data from thiazole, isatin, and phthalimide derivatives, reported in the literature between 2015 and 2022, with in vivo anticancer activity and clinical trials. A bibliographic search was carried out in the PUBMED, MEDLINE, ELSEVIER, and CAPES PERIODIC databases, selecting relevant works for each pharmacophoric group with in vivo antitumor activity in the last 6 years. In our study, 68 articles that fit the scope were selected and critically analyzed. These articles were organized considering the type of antitumor activity and their year of publication. Some compounds reported here demonstrated potent antitumor activity against several tumor types. This review allowed us to highlight works that reported promising structures for the treatment of various cancer types and also demonstrated that the privileged structures thiazole, isatin and phthalimide are important in the design of new syntheses and molecular optimization of compounds with antitumor activity.

Pleurotus pulmonarius polysaccharides inhibit glioma growth through the Hippo signaling pathway and regulate the structure of gut microbiota

Pleurotus pulmonarius (Fr.) is an edible and medicinal fungus. Here, we isolated polysaccharides from P. pulmonarius and evaluated their physicochemical properties, anti-tumor activity, and gut microbiota regulation. Freeze-dried powder of P. pulmonarius fruiting body polysaccharide (PFP) is a heteropolysaccharide, mainly composed of galactose (295.52 μg/mg). PFP significantly inhibited glioma cell survival in vitro and U251 glioma cell tumor growth in nude mice (inhibition rate, 53.70%). PFP inhibited YAP1 and TAZ protein expression levels, upregulated those of MST1 and LAST1, regulated Hippo signaling, stimulated E-cadherin, and downregulated N-cadherin proteins, inhibiting tumor migration. PFP downregulated Bcl-2 protein expression, upregulated that of Cleaved Caspase 3, and induced tumor cell apoptosis. PFP regulated gut microbiota structure in tumor-bearing nude mice and increased the relative abundance of beneficial bacteria. In summary, PFP is a natural, safe, and non-toxic anti-cancer drug, and a potential probiotic. Our data provide theoretical guidance for the treatment of glioma.

Recent Advances in the Development of RET Inhibitors

Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase, causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions. Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib were approved by FDA for the treatment of RET-altered tumors. Objective: Recently reported RET inhibitors were reviewed to provide an overview of the development of novel RET inhibitors. Methods: Literatures, patents, and conference proceedings published in the past five years were collected. Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzymebased and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected RET inhibitors were described. Results: Great efforts have been spent on the development of RET inhibitors, leading to increased RETtargeted therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8- month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants, TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies. Conclusion: Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three promising strategies to address the potential drug resistance of RET.

Heteroaromatization of Coumarin Part I: Design, Synthesis, Reactions, Antitumor Activities of Novel Pyridine and Naphthyridine Derivatives.

A novel series of chromen-3-yl-pyridine moieties were synthesized. IR, NMR, and MS spectroscopy were used to confirm the structure of these novel compounds and study antitumor activity of these compounds. The structure-activity relationship investigation demonstrated that 2,4-diamino- 5-(3-methoxyphenyl)-7-(2-oxo-2H-chromen-3-yl)-1,8-naphthyridine-3-carbonitrile (16), naphthyridine- 3-carbonitrile derivatives 17, 18 and pyrido[2,3-d]pyrimidine derivative 12 were found to be more effective, while compounds 5a,b, 9c, 11, 13 and 14 showed moderate activity for antitumor activities. The objective was to design a series of new chromen-3-yl-pyridine and pyrido[2,3-d]pyrimidine derivatives and study the antitumor of these compounds. The condensation reaction of 3-acetyl-2H-chromen-2-one with 3-methoxy benzaldehyde and malononitrile or ethyl cyanoacetate in the presence of ammonium acetate and acetic acid under reflux to give the corresponding chromen-3-yl pyridine-3-carbonitrile derivatives. In this study, the antitumor activity of the synthesized compounds chromen-3-yl-pyridine derivatives has been determined for the broad spectrum of cytotoxic activity toward the investigated three cell lines and 5-Fluorouracil, as reference drugs. A series of new chromen-3-yl-pyridine and pyrido[2,3-d]pyrimidine derivatives were synthesized in this work. All compounds were evaluated for cytotoxic activity.

Mechanistic evaluation of myristicin on apoptosis and cell cycle regulation in breast cancer cells.

The current study was focused on the anticancer activity of myristicin against MCF-7 human breast cancer (BC) cells. BC is the most common and leading malignant disease in women worldwide. Now-a-days, various conventional therapies are used against BC and still represent a chief challenge because those treatments fail to differentiate normal cells from malignant cells, and they have severe side effects also. So, there is a need develop new therapies to decrease BC-related morbidity and mortality. Myristicin, a 1‑allyl‑5‑methoxy‑3, 4‑methylenedioxybenzene, is a main active aromatic compound present in various spices, such as nutmeg, mace, carrot, cinnamon, parsely and some essential oils. Myristicin has a wide range of effects, including antitumor, antioxidative and antimicrobial activity. Nevertheless, the effects of myristicin on human BC cells remain largely unrevealed. The cytotoxicity effect of myristicin on MCF‑7 cells was increased dose dependently detected by (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Lactate Dehydrogenase assays. Myristicin was found to be significantly inducing the cell apoptosis, as compared to control, using acridine orange/ethidium bromide, Hoechst stain and annexin V. Moreover, it activates cell antimigration, intracellular reactive oxygen species generation and cell cycle arrest in the G1/S phase. In addition, myristicin induces the expression of apoptosis and cell cycle genes (Caspases8, Bax, Bid, Bcl2, PARP, p53, and Cdk1) was demonstrated by quantitative polymerase chain reaction and apoptosis proteins (c-PARP, Caspase 9, Cytochrome C, PDI) expression was also analyzed with western blot. Overall, we illustrated that myristicin could regulate apoptosis signaling pathways in MCF-7 BC cells.

Medicinal Properties of Crotalaria burhia: A Review

Background: Natural products have a crucial role in the discovery and development of drug molecules. The secondary metabolites derived from the plant have potential therapeutic value and reveal many pharmacological effects. Crotalaria burhia Buchham, a Leguminaceae herb, is mostly present in arid parts of India, Pakistan, China, and Afghanistan. Shinio, Bhip, Bhata, Ghugato, and Ban Sutra are just a few of the names it goes by. It is used to cure gout, eczema, hydrophobia, and inflammation. Plant root porridge is used for typhoid, wounds and cuts, rheumatism, flatulence, earaches, nasal bleeding, and stone problems. The powder form of the plant is used for digestive disorders. The plant has potent pharmacological activity and is also carcinogenic and anticarcinogenic in nature. Various phytoconstituents are present, like tannins, amino acids, alkaloids, steroids, triterpenoids, mucilage, flavonoids, gum, polyphenols, anthraquinones, carbohydrates, glycosides, and saponins. Croburhine is a novel pyrrolizidine alkaloid obtained from it. This review focuses on the existing knowledge of the phytochemistry and pharmacological action of C. burhia, which will provide broad information for a proper assessment of the plant as a medicinal agent. Methods: The experimental analysis and data reported on the species of Crotalaria were reviewed from 2005 to 2022. Various databases were used as article sources, like Medline and Pubmed, and a literature review was done using the keywords Crotalaria burhia, habitat, species, pharmacological action, and traditional uses. Result: On the basis of our perception, we have stated that the species Crotalaria burhia is a golden herb that possesses potent pharmacological activities. It is widely used as a conventional drug for the cure of various diseases, but its active constituents need to be evaluated more for future drug development and pharmacological action. Conclusion: There were a total of 21 research articles about the phytochemical screening of herbs, which showed the presence of different active constituents like alkaloids, tannins, flavonoids, steroids, glycosides, mucilage, gum, polyphenols, carbohydrates, terpenoids, etc., which are responsible for different pharmacological activities like antioxidant, antimicrobial, anti-inflammatory, antinociceptive, antihypertensive, antitumor, and analgesic activity.

A Comprehensive Review on Biological and Chemical Diversity in Aesculus L. Genus (Sapindaceae)

Abstract: Aesculus L. is a genus of 12 to 19 woody species, representing one of the most acclaimed examples of inter-continental incoherence of the plants native to temperate regions of the Northern Hemisphere. It is traditionally valued in Ayurveda and the Chinese system of medicine for its various species that possess antitumor, cardioprotective, anti-inflammatory and neuroprotective activities. Current studies on this genus have revealed the presence of specific saponins with a multispectrum of pharmacological actions and therapeutic applications. A repertoire of literature related to the biological, taxonomical, phytochemical and ethnopharmacological aspects of Aesculus genus and its uses in different indigenous populations was explored. An inventory of all the species of this genus that were found to be useful as per ethnopharmacological literature was prepared. The ethnobotany, phytochemistry and pharmacology of the individual species are outlined in this review. The extensive information cited here has adduced the likely areas where the important species of this genus can illustrate significant therapeutic intervention in the management of chronic disorders including diabetes, hypercholesterolemia and cancer. The wide range of its pharmacological actions is attributed to the distinct phytochemicals occurring in the species, especially the triterpenoidal saponins like aescin. This review amplifies the recent studies on phytochemical and pharmacological aspects, which alludes that these species have noteworthy therapeutic potential.

Mg alloys with antitumor and anticorrosion properties for orthopedic oncology: A review from mechanisms to application strategies.

As a primary malignant bone cancer, osteosarcoma (OS) poses a great threat to human health and is still a huge challenge for clinicians. At present, surgical resection is the main treatment strategy for OS. However, surgical intervention will result in a large bone defect, and some tumor cells remaining around the excised bone tissue often lead to the recurrence and metastasis of OS. Biomedical Mg-based materials have been widely employed as orthopedic implants in bone defect reconstruction, and, especially, they can eradicate the residual OS cells due to the antitumor activities of their degradation products. Nevertheless, the fast corrosion rate of Mg alloys has greatly limited their application scope in the biomedical field, and the improvement of the corrosion resistance will impair the antitumor effects, which mainly arise from their rapid corrosion. Hence, it is vital to balance the corrosion resistance and the antitumor activities of Mg alloys. The presented review systematically discussed the potential antitumor mechanisms of three corrosion products of Mg alloys. Moreover, several strategies to simultaneously enhance the anticorrosion properties and antitumor effects of Mg alloys were also proposed.

MiR-26a is a Key Therapeutic Target with Enormous Potential in the Diagnosis and Prognosis of Human Disease.

MicroRNA-26a (miR-26a) belongs to small non-coding regulatory RNA molecules emerging as fundamental post-transcriptional regulators inhibiting gene expression that plays vital roles in various processes of human diseases such as depression, renal ischemia and reperfusion injury, liver injury and some refractory cancer. In this review, we expound on the results of studies about miR-26a with emphasis on its function in animal models or in vitro cell culture to simulate the most common human disease in the clinic. Furthermore, we also illustrate the underlying mechanisms of miR-26a in strengthening the antitumor activity of antineoplastic drugs. Importantly, dysregulation of miR-26a has been related to many chronic and malignant diseases, especially in neurological disorders in the brain such as depression and neurodegenerative diseases as well as cancers such as papillary thyroid carcinoma, hepatocellular carcinoma and so on. It follows that miR-26a has a strong possibility to be a potential therapeutic target for the treatment of neurological disorders and cancers. Although the research of miRNAs has made great progress in the last few decades, much is yet to be discovered, especially regarding their underlying mechanisms and roles in the complex diseases of humans. Consequently, miR-26a has been analyzed in chronic and malignant diseases, and we discuss the dysregulation of miR-26a and functional roles in the development and pathogenesis of these diseases, which is very helpful for understanding their mechanisms as new biomarkers for diagnosing and curing diseases in the near future.

Discovery of novel EGFR-PROTACs capable of degradation of multiple EGFR-mutated proteins

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI–H1975 cells, and NCI–H1975-TM cells (IC50 = 0.009 μM, 0.49 μM and 3.24 μM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 μM and 0.63 μM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

An article reviews of anti-cataract activity of hydroalcoholic extract of Annona squamosa leaves

Other medicines and natural remedies have been used for the treatment and health of people since ancient times. Medicinal plants are considered useful and of the most important purpose. It can be applied to botanical medicines, nutraceuticals, medicines, food products, cosmetics, etc. There is an increasing demand for. Custard apples. It is a versatile tree whose fruit is edible and a source of medicine and products. It is used as antioxidant, antidiabetic, hepatoprotective, cytotoxic activity, genotoxicity, antitumor activity, anti-inflammatory drug. Cataract is nothing but visual impairment caused by a defect in the lens. It is one of the causes of blindness worldwide; It accounts for approximately 42% of all blindness. One significant risk factor for the development of posterior subcapsular cataracts is long-term glucocorticoid usage. The preventive and therapeutic effects of many herbs such as onion, Chinese cinnamon and ginkgo, which have protective properties against cataracts, have been reported. This review demonstrates the therapeutic potential of custard apple leaf extract as an anti-cataract effec

Chiral Hydroxy Metabolite of Mebendazole: Analytical and Semi-Preparative High-Performance Liquid Chromatography Resolution and Chiroptical Properties

Mebendazole (MBZ) is a benzimidazole carbamate anthelmintic used worldwide for the treatment and prevention of parasitic disorders in animals and humans. A large number of in vivo and in vitro studies have demonstrated that MBZ also has anticancer activity in multiple types of cancers. After oral administration, the phenylketone moiety of MBZ is rapidly reduced to the hydroxyl group to form the chiral hydroxy metabolite (MBZ-OH). To the best of our knowledge, there is no information in the literature on the stereochemical course of transformation and the anthelmintic and antitumor activity of individual enantiomers of MBZ-OH. In the present study, we describe in detail the direct HPLC resolution of MBZ-OH on a 100 mm × 4.6 mm Chirapak IG-3 column packed with 3 μm silica particles containing amylose (3-chloro-5-methylphenylcarbamate) as a selector. At 25 °C and using pure methanol as the mobile phase, the enantioseparation and resolution factors were 2.38 and 6.13, respectively. These conditions were scaled up at a semi-preparative scale using a 250 mm × 10 mm Chiralpak IG column to isolate multi-milligram amounts of both enantiomeric forms of the chiral metabolite. The chiroptical properties of the collected enantiomers were determined and, through a theoretical study, were related to the more stable conformations of MBZ-OH. The first and second eluted enantiomers were dextrorotatory and levorotatory, respectively, in dimethylformamide solution. Finally, by recording the retention factors of the enantiomers as the water content in the water–acetonitrile mobile phases was progressively varied, U-shaped retention maps were generated, indicating a dual and competitive hydrophilic interaction liquid chromatography and reversed-phase liquid chromatography retention mechanism on the Chirapak IG-3 chiral stationary phase.

Gold-Catalyzed Cascade Reaction of Yne-Enones with Iminooxindoles, Access to 3,2'-Pyrrolidinyl-Spirooxindole Derivatives.

Herein, a gold-catalyzed cascade reaction of yne-enones with iminooxindoles has been developed through a cascade cycloisomerization/(3 + 2) annulation process. This approach provides a straightforward and efficient route for the synthesis of functionalized 3,2'-pyrrolidinyl-spirooxindoles in high reactivity and broad substrate scope with excellent cis-selectivity. Moreover, the subsequent functionalization of furan units allows for the diverse synthesis of spirooxindole derivatives, which have demonstrated good antitumoral activity.

Advances in CAR-NK cell therapy for lung cancer: is it a better choice in the future?

Lung cancer remains one of the leading causes of cancer-related mortality worldwide necessitating the development of innovative therapeutic strategies. Chimeric antigen receptor (CAR) natural killer (NK) cell therapy represents a promising advancement in the field of oncology offering a novel approach to target and eliminate tumor cells with high specificity and reduced risk of immune-related adverse effects. This paper reviews the mechanism, potential targets, and recent advances in CAR-NK cell therapy for lung cancer, including the design and engineering of CAR-NK cells, preclinical studies, and the outcomes of early-phase clinical trials. We highlight the unique advantages of using NK cells, such as their innate ability to recognize and kill cancer cells and their reduced potential for inducing graft-versus-host disease (GvHD) and cytokine release syndrome (CRS) compared to CAR T-cell therapies. Results from recent studies demonstrate significant antitumor activity in lung cancer models with improved targeting and persistence of CAR-NK cells observed in vitro and in vivo. Finally, we discuss the challenges in optimizing CAR-NK cell therapies, including the potential resistance mechanisms. The paper concludes with an outlook on the future directions of CAR-NK cell research and its implications for lung cancer treatment emphasizing the importance of continued innovation and collaboration in the field.

Antitumor activity of Z15-0-2, a bispecific nanobody targeting PD-1 and CTLA-4.

The combination of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies has potential for enhancing clinical efficacy. We described the development and antitumor activity of Z15-0, a bispecific nanobody targeting both the PD-1 and CTLA-4 pathways simultaneously. We designed and optimized the mRNA sequence encoding Z15-0, referred to as Z15-0-2 and through a series of in vitro and in vivo experiments, we established that the optimized Z15-0-2 mRNA sequence significantly increased the expression of the bispecific nanobody. Administration of Z15-0-2 mRNA to tumor-bearing mice led to greater inhibition of tumor growth compared to controls. In aggregate, we introduced a novel bispecific nanobody and have re-engineered it to boost expression of mRNA, representing a new drug development paradigm.

The Antimicrobial PeptideTilapia Piscidin 4 Induced the Apoptosis of Bladder Cancer Through ERK/SIRT1/PGC-1α Signaling Pathway.

Marine antimicrobial peptides have been demonstrated in numerous studies to possess anti-cancer properties. This research investigation aimed to explore the fundamental molecular mechanisms underlying the antitumor activity of Tilapia piscidin 4 (TP4), an antimicrobial peptide, in human bladder cancer. TP4 exhibited a remarkable inhibitory effect on the proliferation of bladder cancer cells through cell cycle arrest at the G2/M phase. Additionally, TP4 upregulated the expression of cleaved caspase-3, caspase-9, and PARP, leading to the activation of apoptotic pathways in bladder cancer cells. TP4 exhibit a marked rise in mitochondria reactive oxygen species, leading to the subsequent loss of potential for the mitochondrial membrane. Furthermore, the inhibition of mitochondrial oxidative phosphorylation resulted in a decrease in downstream ATP production. Meanwhile, TP4-treated bladder cancer cells showed an increase in Bax and ERK but a decrease in SIRT1, PGC-1α, and Bcl2. ERK activation, SIRT1/PGC-1α-axis, and TP4-induced apoptosis were all significantly reversed by the ERK inhibitor SCH772984. Finally, the inhibitory effect of TP4 on tumor growth has been confirmed in a zebrafish bladder cancer xenotransplantation model. These findings suggest that TP4 may be a potential agents for human bladder cancer through apoptosis induction, ERK activation, and the promotion of SIRT1-mediated signaling pathways.

Synergistic Antitumor Activity of Talazoparib and Temozolomide in Malignant Rhabdoid Tumors

Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response.

HSP70-mediated mitochondrial dynamics and autophagy represent a novel vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC), the most prevalent type of pancreatic cancer, is one of the deadliest forms of cancer with limited therapy options. Overexpression of the heat shock protein 70 (HSP70) is a hallmark of cancer that is strongly associated with aggressive disease and worse clinical outcomes. However, the underlying mechanisms by which HSP70 allows tumor cells to thrive under conditions of continuous stress have not been fully described. Here, we report that PDAC has the highest expression of HSP70 relative to normal tissue across all cancersanalyzed. Furthermore, HSP70 expression is associated with tumor grade and is further enhanced in metastatic PDAC. We show that genetic or therapeutic ablation of HSP70 alters mitochondrial subcellular localization, impairs mitochondrial dynamics, and promotes mitochondrial swelling to induce apoptosis. Mechanistically, we find that targeting HSP70 suppresses the PTEN-induced kinase 1 (PINK1) mediated phosphorylation of dynamin-related protein 1 (DRP1). Treatment with the HSP70 inhibitor AP-4-139B was efficacious as a single agent in primary and metastatic mousemodels of PDAC. In addition, we demonstrate that HSP70 inhibition promotes the AMP-activated protein kinase (AMPK) mediated phosphorylation of Beclin-1, a key regulator of autophagic flux. Accordingly, we find that the autophagy inhibitor hydroxychloroquine (HCQ) enhances the ability of AP-4-139B to mediate anti-tumor activity in vivo. Collectively, our results suggest that HSP70 is a multi-functional driver of tumorigenesis that orchestrates mitochondrial dynamics and autophagy. Moreover, these findings support the rationale for concurrent inhibition of HSP70 and autophagy as a novel therapeutic approach for HSP70-driven PDAC.

Prognostic impact of corticosteroid and tocilizumab use following chimeric antigen receptor T-cell therapy for multiple myeloma.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017-March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36-1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Inhibition of NF-kB and COX-2 by andrographolide regulates the progression of cervical cancer by promoting PTEN expression and suppressing PI3K/AKT signalling pathway

In the face of recent advances in Cervical cancer (CC) treatment, therapeutic and surgical procedures for CC management are still inadequate. In the current study for the first time Andrographolide (Andro) has been explored for its multitarget therapeutic efficacy on NF-kB, COX-2, and PI3K/AKT expressions together in CC. The expression levels of NF-kB, COX-2, PI3K and PTEN in the CC patient samples, both at mRNA and protein levels have shown significant association with poor survival and increased tumor aggressiveness. The binding efficacy of Andro was investigated using molecular docking and molecular dynamic simulations, and the protein and ligand complex for NF-kB and COX-2 has shown high binding energy. Andro displayed cytotoxicity by impeding the in-vitro proliferation of CC cells. Andro significantly supressed the NF-kB, COX-2, and PI3K expression and enhanced the expression levels of PTEN at protein levels in-vitro. Andro induced apoptosis in a dose dependent manner and significantly inhibited the migration and invasion of CC cells. Andro exhibited similar activity in-vivo and suppressed the CC tumor growth in xenograft C57BL/6 mice model. The anti-tumor activity of Andro, both in-vitro and in-vivo has shown considerable downregulation of NF-kB and COX-2 and induced apoptosis through impeding the PI3K/AKT signalling pathway. These findings from the above study projects, administration of Andro as an effective alternate safe compound to curtail and impede cervical cancer progression.